Overview

Also Known As:129 E6-AP-, 129 AS

E6-AP mutant mice carry a paternally imprinted Ube3a (ubiquitin protein ligase E3A) knock-out mutation and may be useful in studies of Angelman syndrome (AS).

Genetic background-dependent differences in the behavioral, EEG activity and seizure phenotypes are observed - see C57BL/6 Ube3a maternal deletion mice ("B6 AS" ; Stock No. 016590) and 129 Ube3a maternal deletion mice ("129 AS" ; Stock No. 004477).

Donating Investigator

Dr. Arthur Beaudet, Baylor College of Medicine

Genetic overview

Genetic Background	Generation

Ube3a^tm1Alb

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Ube3a	ubiquitin protein ligase E3A

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Mice that are heterozygous for the targeted mutation are viable and fertile. There is a reduced viability (9%) prior to weaning for homozygous offspring from heterozygous parents. Surviving homozygous mice display delayed growth and motor dysfunctions. No gene product (mRNA) is detected by Northern blot analysis in homozygous ES cells. In situ hybridization reveals no detectable expression in hippocampal neurons and Purkinje cells of heterozygotes with a maternal deficiency. Due to imprinting, with preferential expression of the maternal allele, heterozygous mice with a maternal deficiency display the phenotype while heterozygous mice with a paternal deficiency do not. Heterozygous mice with the maternal deficiency display reduced motor coordination, impaired long-term potentiation, and context-dependent learning abnormalities. Homozygous mice and heterozygous mice with a maternal deficiency have increased Purkinje cell cytoplasmic levels of TRP53, transformation related protein 53, and an increased susceptibility to tonic clonic seizures induced by handling. This mutant mouse strain represents a model that may be useful in studies of Angelman syndrome.

Mice with this Ube3a knock-out mutation are available on different genetic backgrounds - either C57BL/6 (Stock No. 016590) or 129 (Stock No. 004477). Born et al. 2017 Sci Rep. 7:8451 [PMID:28814801] describes genetic background differences in the behavioral, EEG activity and seizure phenotypes for these mutant mice. In summary, C57BL/6 Ube3a maternal deletion mice ("B6 AS") displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. 129 Ube3a maternal deletion mice ("129 AS") demonstrated limited behavioral abnormalities, performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. See that publication for more specific details.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes and a loxP site was used to disrupt a 3 kb sequence including exon 2. The construct was electroporated into 129S7/SvEvBrd-Hprt^b-m2-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to 129 mice.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Jiang YH; Armstrong D; Albrecht U; Atkins CM; Noebels JL; Eichele G ; Sweatt JD ; Beaudet AL. 1998. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation Neuron 21(4):799-811PubMed: 9808466 MGI: J:50811

View All References

Genetics

Ube3a^tm1Alb

Allele Symbol: Ube3a^tm1Alb

Allele Name	targeted mutation 1, Arthur L Beaudet
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	E6-AP^-; E6AP^-; Ube3A KO
Gene Symbol and Name	Ube3a, ubiquitin protein ligase E3A
Gene Synonym(s)
Strain of Origin	129S7/SvEvBrd-Hprt^b-m2
Chromosome	7
Molecular Note	A 3kb genomic region including exon 2 was replaced with a neo-loxP-hprt cassette via homologous recombination, resulting in deletion of 100 N-terminal amino acids in the encoded protein and a frameshift inactivating all putative protein isoforms. Homozygous mutant animals were identified by Southern blot and PCR genotype analysis.
Mutations Made By	Dr. Arthur Beaudet, Baylor College of Medicine

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Angelman syndrome

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Ube3a^tm1Alb related

Neurobiology Research
- Angelman syndrome

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Ube3a^tm1Alb/Ube3a^tm1Alb
involves: 129S7/SvEvBrd * C57BL/6

behavior/neurological phenotype

audiogenic seizures
- Background Sensitivity - observed in 20-30% of mice with maternal deficiency

integument phenotype

abnormal mammary gland growth during pregnancy
- mammary gland development in ovarectomized females treated with progesterone and estradiol to mimic pregnance was comparable to wild-type at 12 and 14 weeks
- some females show increased ductal branching and lobuloalveolar development compared to wild-type controls, but penetrance of this phenotype is not consistent

mortality/aging

postnatal lethality
- Background Sensitivity - slight reduction in survival prior to weaning compared to wild-type

nervous system phenotype

audiogenic seizures
- Background Sensitivity - observed in 20-30% of mice with maternal deficiency

reproductive system phenotype

abnormal mammary gland growth during pregnancy
- some females show increased ductal branching and lobuloalveolar development compared to wild-type controls, but penetrance of this phenotype is not consistent
- mammary gland development in ovarectomized females treated with progesterone and estradiol to mimic pregnance was comparable to wild-type at 12 and 14 weeks

decreased ovary weight
- at 8-10 weeks of age, ovaries weigh ~30% less than wild-type ovaries; at later time points, difference is not observed

abnormal ovarian folliculogenesis
- ovaries from 3-week old females treated with PMSG and hCG have fewer developing follicles

decreased litter size
- litter size is ~48% lower in homozygous females compared to wild-type
- litters sired by homozygous males with wild-type females have ~34% fewer pups/litter

impaired luteinization
- ovaries from 3-week old females treated with PMSG and hCG are relatively deficient in luteinized cells

impaired sperm capacitation
- sperm has lower ability to penetrate oocytes in vitro compared to controls

decreased prostate gland weight
- prostate gland weight is lower in castrated mutants treated with testosterone, compared to control castrated males treated with testosterone

oligozoospermia
- epididymal sperm counts are ~38% lower than in wild-type males

reduced male fertility
- total number of offspring sired by homozygous males with wild-type females is reduced compared to wild-type males

decreased oocyte number
- oocyte numbers are~68% less in 3 week old homozygous females treated with PMSG and hCG

decreased testis weight
- in 12 week old mice, testis weight is reduced by ~24% compared to wild-type

decreased uterus weight
- uterine wet weight is ~35% lower in mutant ovarectomized females after estradiol treament compared to matched controls

reduced female fertility
- female are subfertile

cellular phenotype

decreased oocyte number
- oocyte numbers are~68% less in 3 week old homozygous females treated with PMSG and hCG

oligozoospermia
- epididymal sperm counts are ~38% lower than in wild-type males

endocrine/exocrine gland phenotype

decreased prostate gland weight
- prostate gland weight is lower in castrated mutants treated with testosterone, compared to control castrated males treated with testosterone

abnormal ovarian folliculogenesis
- ovaries from 3-week old females treated with PMSG and hCG have fewer developing follicles

abnormal mammary gland growth during pregnancy
- some females show increased ductal branching and lobuloalveolar development compared to wild-type controls, but penetrance of this phenotype is not consistent
- mammary gland development in ovarectomized females treated with progesterone and estradiol to mimic pregnance was comparable to wild-type at 12 and 14 weeks

decreased testis weight
- in 12 week old mice, testis weight is reduced by ~24% compared to wild-type

decreased ovary weight
- at 8-10 weeks of age, ovaries weigh ~30% less than wild-type ovaries; at later time points, difference is not observed

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd * C57BL/6

cellular phenotype

paternal imprinting
- this allele is maternally inherited and silenced in males by imprinting
- inheritance of the maternal Ube3a^tm1Alb allele results in much more severe phenotypic effects compared to inheritance of the paternal allele

growth/size/body region phenotype

decreased body weight
- mice with maternal Ube3a deficiency (inheriting null allele from mother) have significant reduction in body weight at 18 days of age; by 4 months, difference is gone

increased body weight
- starting at 3 months when this allele is inherited maternally

behavior/neurological phenotype

abnormal emotion/affect behavior
- impaired performance in a marble burying test when this allele is inherited maternally

impaired contextual conditioning behavior
- reduced freezing when this allele is inherited maternally

impaired coordination
- on an accelerating rotarod, wire hang test and dowel test when this allele is inherited maternally
- mice with maternal deficiency cannot stay on rotating rod as long as wild-type (37.9 sec vs 72.3 sec)

abnormal motor learning
- mice with maternal deficiency exhibit impaired motor learning in accelerating rod test, staying on apparatus for significantly less time (193 sec) than wild-type (439 sec) on first day; by day 4, time difference was not significant

hypoactivity
- when this allele is inherited maternally

abnormal contextual conditioning behavior
- mice with maternal deficiency show deficits in context-dependent fear conditioning compared to littermates

audiogenic seizures
- Background Sensitivity - observed in 20-30% of mice with maternal deficiency on hybrid background
- mice with maternal deficiency are substantially more susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizures

tonic-clonic seizures
- occasionally observed in mice with maternal deficiency

abnormal gait
- mice with maternal deficiency have shorter step distance (5 cm) and reduced left-right step alternation coefficient (0.08) compared to wild-type littermates(5.9 cm, 0.14)

absence seizures
- longer abnormal EEG episodes in mice with maternal deficiency are accompanied by behavioral immobility which is characteristic of absence seizures

nervous system phenotype

abnormal cerebral cortex morphology
- reduced in weight in mice at 18 days through 4 months of age with maternal deficiency

abnormal dendrite morphology
- pyramidal dendrites exhibit varicosities along the secondary dendritic shaft unlike in wild-type mice
- dendrites are thinner than in wild-type mice
- when inherited maternally, the dendritic spines on cerebellar Purkinje cells and hippocampal and cortical pyramidal neurons exhibit reduced spine density (1.228+/-0.055 spines per um compared to 1.614+/-0.076 spines per um in wild-type mice), a reduced number of spines along cortical apical dendrites (0.882+/-0.057 spines per um compared to 1.172+/-0.044 spines per um in wild-type mice), and reduced spine length (1.017+/-0.0454 um compared to 1.16+/-0.0038 um in wild-type mice)
- mber of spines along cortical apical dendrites (0.882+/-0.057 spines per um compared to 1.172+/-0.044 spines per um in wild-type mice), and reduced spine length (1.017+/-0.0454 um compared to 1.16+/-0.0038 um in wild-type mice)

abnormal long term potentiation
- decaying LTP when this allele is inherited maternally

absence seizures
- longer abnormal EEG episodes in mice with maternal deficiency are accompanied by behavioral immobility which is characteristic of absence seizures

audiogenic seizures
- mice with maternal deficiency are substantially more susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizures
- Background Sensitivity - observed in 20-30% of mice with maternal deficiency on hybrid background

small cerebellum
- reduced in weight at 18 days through 4 months of age in mice with maternal deficiency

abnormal nervous system electrophysiology

abnormal brain wave pattern
- longer abnormal EEG episodes in mice with maternal deficiency are accompanied by behavioral immobility which is characteristic of absence seizures
- EEG activity is abnormal with abundant bilateral 3 sec spike activity mixed with polyspike and slow wave discharges

reduced long term potentiation
- hippocampal slices from mice with maternal deficiency display reduced LTP; high frequency stimulation only produces transient potentiation (short term potentiation) compared to LTP produced in wild-type

tonic-clonic seizures
- occasionally observed in mice with maternal deficiency

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd * C57BL/6J

homeostasis/metabolism phenotype

increased dopamine level
- DOPAC levels are increased in the striatum and midbrain
- mice with maternal deficiency exhibit increased dopamine levels in the striatum and cortex

abnormal adrenaline level
- mice with maternal deficiency (inheriting the null allele from the mother) exhibit increased epinephrine levels in the midbrain

increased serotonin level
- mice with maternal deficiency exhibit increased 5HT (serotonin) levels in the frontal cortex and striatum

nervous system phenotype

abnormal adrenaline level
- mice with maternal deficiency (inheriting the null allele from the mother) exhibit increased epinephrine levels in the midbrain

increased serotonin level
- mice with maternal deficiency exhibit increased 5HT (serotonin) levels in the frontal cortex and striatum

The following phenotype relates to a compound genotype created using this strain

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd

behavior/neurological phenotype

audiogenic seizures
- Background Sensitivity - observed in 18% of mice with paternal deficiency and 85% (17/20) with maternal deficiency compared to mice on 129/B6 background
- mice with maternal deficiency are susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizures

tonic-clonic seizures
- occasionally observed in mice with maternal deficiency

nervous system phenotype

audiogenic seizures
- Background Sensitivity - observed in 18% of mice with paternal deficiency and 85% (17/20) with maternal deficiency compared to mice on 129/B6 background
- mice with maternal deficiency are susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizures

tonic-clonic seizures
- occasionally observed in mice with maternal deficiency

Genotype: Ube3a^tm1Alb/Ube3a^tm1Alb
involves: 129S7/SvEvBrd

behavior/neurological phenotype

audiogenic seizures
- Background Sensitivity - observed in all mice (5/5)
- mice with maternal deficiency are susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizure

abnormal posture
- mice often exhibit stationary posture when lifted by tail

bradykinesia
- surviving mice are less active than littermates

limb grasping
- mice demonstrate hindlimb clasping when lifted by tail

growth/size/body region phenotype

postnatal growth retardation
- surviving mice are often growth-retarded

mortality/aging

postnatal lethality, incomplete penetrance
- Background Sensitivity - substantial reduction in postnatal survival compared to mice on 129/B6 background, is seen, with death frequently observed during the first 48 hours postnatal (about 80%)

nervous system phenotype

audiogenic seizures
- Background Sensitivity - observed in all mice (5/5)
- mice with maternal deficiency are susceptible to audiogenic seizures characterized by running and leaping followed by tonic clonic seizure

References

Jiang YH; Armstrong D; Albrecht U; Atkins CM; Noebels JL; Eichele G ; Sweatt JD ; Beaudet AL. 1998. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation Neuron 21(4):799-811PubMed: 9808466 MGI: J:50811

Additional - Ube3a^tm1Alb related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Ube3a Alternate 3
- Genotyping resources and troubleshooting
Breeding Considerations

The strain is maintained as a heterozygote due to variable homozygous lethality. Expected coat color is Agouti.
- Additional Breeding and Husbandry Support
Citation
When using the 129 E6-AP- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004477 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous or Wild-type for Ube3a<tm1Alb> (paternally imprinted)

Related Products and Services

Frozen Mouse Embryo	129-Ube3a<tm1Alb>/J Frozen Embryos	$2595.00
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Frozen Mouse Embryo	129-Ube3a<tm1Alb>/J Frozen Embryos	$3373.50
Frozen Mouse Embryo	129-Ube3a<tm1Alb>/J Frozen Embryos	$3373.50

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:129 E6-AP-, 129 AS

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Ube3atm1Alb

Allele Symbol: Ube3atm1Alb

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Ube3atm1Alb related

Mammalian Phenotype Terms by Genotype

Genotype: Ube3atm1Alb/Ube3atm1Albinvolves: 129S7/SvEvBrd * C57BL/6

behavior/neurological phenotype

integument phenotype

mortality/aging

nervous system phenotype

reproductive system phenotype

cellular phenotype

endocrine/exocrine gland phenotype

Genotype: Ube3atm1Alb/Ube3a+involves: 129S7/SvEvBrd * C57BL/6

cellular phenotype

growth/size/body region phenotype

behavior/neurological phenotype

nervous system phenotype

Genotype: Ube3atm1Alb/Ube3a+involves: 129S7/SvEvBrd * C57BL/6J

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Ube3atm1Alb/Ube3a+involves: 129S7/SvEvBrd

behavior/neurological phenotype

nervous system phenotype

Genotype: Ube3atm1Alb/Ube3atm1Albinvolves: 129S7/SvEvBrd

behavior/neurological phenotype

growth/size/body region phenotype

mortality/aging

nervous system phenotype

References

Additional - Ube3atm1Alb related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Ube3a^tm1Alb

Allele Symbol: Ube3a^tm1Alb

Genotype: Ube3a^tm1Alb related

Genotype: Ube3a^tm1Alb/Ube3a^tm1Alb
involves: 129S7/SvEvBrd * C57BL/6

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd * C57BL/6

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd * C57BL/6J

Genotype: Ube3a^tm1Alb/Ube3a⁺
involves: 129S7/SvEvBrd

Genotype: Ube3a^tm1Alb/Ube3a^tm1Alb
involves: 129S7/SvEvBrd

Additional - Ube3a^tm1Alb related